Demethylation of phenolic ethers is done by a number of methods. Usually boron tri bromide (BBr3), pyridinium chloride (pyridine-HCl), Lithium aluminum hydride (LAH), aluminum chloride (AlCl3) as such or with a variety of solvents like petroleum ether, ethyl acetate-HCl, EtSH, L-Selectride (Lithium tri-sec-butyl Hydride), etc., have been used as demethylating agents in the synthesis of different compounds.
The most common reagent for demethylation of phenolic ethers is pyridinium chloride, which provides no regioselectivity. Ijaz et al. (Ind. J. Chem., Sec. B (1994), 33B(3), 288–289), have used pyridinium hydrobromideperbromide for the demethylation of arylmethyl ethers, but there was no regioselectivity in this method. Hwang et al. (Synthetic Comm. (1993), 23(20), 2845–2849), have reported demethylation of p-alkoxy-phenyl methyl ethers with 48% hydrobromic acid in presence of tetrabutyl phosphorus bromide (BU4PBr). Bastow et al. (Bioorg. Med. Chem. (1993), 1(3), 227–234), have demethylated all the four methoxy ethers of colchicine by using 1M BBr3 in dicholoromethane. Among the selective demethylation methods Lal et al. (J. Org. Chem. (1987), 52(6), 1072–1078), have used sodium thioxide (C2H5SNa) in DMF for the demethylation of ortho-methoxy groups in some aromatic alcohols bearing 2,4-dimethoxy and 2, 3, 4-trimethoxy derivatives. Horie et al. (J. Org. Chem. (1987), 52(21), 4702–4709), selectively demethylated 7-hydroxy-3, 5, 8-trimethoxy flavones with aluminum bromide in acetonitrile to 5,7-dihydroxy and 3,7-dihydroxy flavone derivatives. Another demethylation approach was developed by Horie et al. (Chem. Pharm. Bull. (1987), 35(11), 4465–4472), in which they have selectively demethylated ortho-methoxy group in 2, 3, 4, 6-tetra methoxy acetophenone-type moieties by aluminum bromide in acetonitrile. Demettenaere et al. (Tetrahedron (2002), 58, 2163), have reported a similar method in which they have demethylated both the 2,4-dimethoxy groups in a 2, 4, 5-trimethoxy benzaldehyde by using aluminum chloride.
A similar method for regioselective demethylation of 3, 4, 5-trimethoxy benzoic acid has been done by Soreau et al. (U.S. Pat. No. 4,191,841) to 4-hydroxy-3,5-dimethoxy benzoic acid by using an excess of alkali hydroxide in an amount of ethylene glycol.
So far, there is no such report on regioselective demethylation of p-methoxy group in a 3,4-dimethoxy and/or 3, 4, 5-trimethoxy derivatives of benzoic acid esters and diaryl ketone derivatives.